POS0136 COMPLEMENT C1q PROMOTES MITOCHONDRIA RESPIRATION AND SECRETION OF IL-6 and IL-1β BUT NOT TNF-α BY SYNOVIAL MACROPHAGE IN RHEUMATOID ARTHRITIS
Authors: Y. Jiang, B. Wu, T. Huang, Y. Liu, Z. Hu, T. Zhao, Y. Pan, W. Cornelia
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> Complement C1q (C1q), predominantly synthesized by myeloid cells such as macrophages, has elusive functions in the pathogenesis of rheumatic arthritis (RA). Binding to its receptor gC1qR, C1q can activate mitochondria, the dysfunction of which may result in tissue inflammatory disease [1]. Bone marrow derived macrophages in RA patients have elevated OXPHOS activity [2], while the reason remains to be discovered. <h3>Objectives</h3> The objectives of the study were to explore the expression of C1q and its receptor gC1qR in synovial macrophages in RA and whether C1q contributes to tissue inflammation via affecting pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and mitochondria respiration in synovial macrophages. <h3>Methods</h3> Tissue transcriptome analysis for C1q(C1qA, C1qB and C1qC), C1q receptors (including gC1qR) in rheumatoid synovium and and pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) in rheumatoid synovium and synovium macrophages were quantified by RT-PCR. Concentrations of C1q in the plasma of RA and healthy controls (HC) were analyzed by ELISA and the correlation between plasma C1q and disease activty measured by DAS28 were calculated. gC1qR protein expression was detected by flow cytometric analysis and immunoblotting. Synovial macrophages were isolated and stimulated with or without C1q for 24 h. Function of gC1qR was analysed by knockdown experiment using siRNA. Transcripts for inflammatory cytokines were quantified by RT-PCR. Mitochondrial respirometer was evaluated with Seahorse Bioscience XF96 analyzer after C1q treatment or gC1qR knockdown. <h3>Results</h3> C1qA, C1qB,C1qC and gC1qR were all upregulated in both rheumatoid synovium and synovial macrophages compared to healthy controls. Meanwhile, RA patients had a higher level of C1q concentration in plasma, which positively correlated with DAS28. Moreover, an increased expression of gC1qR protein was confirmed by flow cytometric analysis and immunoblotting. Besides, C1q could increase the expression of IL-6 and IL-1β but not TNF-α in synovial macrophages. We also found that C1q could increase basal OCR, ATP-coupled OCR, max respiration and reserve capacity of healthy macrophages. Comparatively, gC1qR knockout could down-regulate mitochondria respiration of RA macrophages. <h3>Conclusion</h3> Synovial macrophages in RA patients have significantly elevated expression of C1q and its receptor gC1qR. C1q could promote mitochondria respiration through gC1qR, thus leading to hyper-metabolism in macrophages from RA patients. C1q could promote synovitis through enhanced pro-inflammatory cytokines IL-6 and IL-1β but not TNF-α secreted by synovial macrophages, which represents a novel therapeutic target in RA. <h3>References</h3> [1]Weyand CM, Goronzy JJ. A Mitochondrial Checkpoint in Autoimmune Disease. Cell Metab 2018; 28: 185-186. [2]M. Zeisbrich, R.E. Yanes, H. Zhang, R. Watanabe, Y. Li, L. Brosig, et al., Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation. Ann Rheum Dis 2018; 77: 1053-1062. <h3>Disclosure of Interests</h3> Yutong Jiang Grant/research support from: Basic and Applied Basic Research Fund Project of Guandong Province [2021A1515111172]., Bowen Wu: None declared, Tao Huang: None declared, Yan Liu: None declared, Zhaolan Hu: None declared, Tuantuan Zhao: None declared, Yunfeng Pan: None declared, Weyand Cornelia: None declared